Preclinical Safety Evaluation of Ophthalmic Viscosurgical Devices in Rabbits and a Novel Mini-Pig Model.

INTRODUCTION: To establish the preclinical safety and equivalency of ophthalmic viscosurgical devices (OVDs) comprised of bacterially sourced sodium hyaluronate (HA) to animal sourced HA using pyrogenicity and aqueous exchange models in rabbits and a novel mini-pig model to evaluate corneal endothelial cell protection in vivo. METHODS: HEALON OVD and HEALON5 OVD containing animal-derived HA and HEALON PRO OVD and HEALON5 PRO OVD containing bacterial-derived HA were used. Two rabbit aqueous exchange studies were conducted where aqueous humor was exchanged with OVDs in six animals each to observe potential ocular inflammation, intraocular pressure (IOP) response, corneal health and pachymetry until 7 days post procedure, as well as overall assessment of the OVDs. Endothelial cell protection was evaluated in a Yucatan mini-pig cataract surgery model where HEALON PRO and HEALON5 PRO OVDs were compared to HEALON and HEALON5 OVDs, respectively. Following cataract surgery with use of OVDs in six animals per study, animals were evaluated for ocular and general health, IOP, corneal thickness, ocular inflammation, and endothelial cell protection on days 1, 3, 7 and 14 post-surgery. RESULTS: All rabbit studies demonstrated equivalence between bacterial-derived and animal-derived OVDs. Mild, post-surgical irritation, IOP increase, and corneal thickness measurements were not significantly different in HEALON PRO OVD and HEALON5 PRO OVD compared to HEALON and HEALON5 OVDs, respectively. The mini-pig model developed to investigate endothelial cell protection was successful in demonstrating equivalence between the OVDs studied. Changes in IOP mirrored actual surgical procedures, while corneal pachymetry and endothelial cell density remained constant for all OVDs used. Slit lamp observations showed expected inflammation following surgical procedures, likely due to challenges encountered during surgical procedures. CONCLUSION: Rabbit pyrogenicity and aqueous exchanged paired with a novel simulated cataract surgery mini-pig model demonstrate equivalence of OVDs regardless of HA source. Albeit with challenges, the mini-pig model was shown to be a promising tool for endothelial cell evaluation during the development of new OVDs for ophthalmic use. FUNDING: Johnson & Johnson Surgical Vision, Inc.

Penetrating and Intrastromal Corneal Arcuate Incisions in Rabbit and Human Cadaver Eyes: Manual Diamond Blade and Femtosecond Laser-Created Incisions.

OBJECTIVES: To compare morphologic differences between freehand diamond or femtosecond laser-assisted penetrating and intrastromal arcuate incisions. METHODS: Freehand diamond blade, corneal arcuate incisions (180° apart, 60° arc lengths) and 150 kHz femtosecond laser (80% scheimpflug pachymetry depth corneal thickness) arcuate incisions were performed in rabbits. Intrastromal arcuate incisions (100 µm above Descemet's membrane, 100 µm below epithelium) were performed in rabbit corneas (energy 1.2 µJ, spot line separation 3 × 3 µm, 90° side cut angle). Eyes were examined by slit lamp and light microscopy up to 47 days post-procedure. Freehand diamond blade penetrating incisions, and femtosecond laser penetrating and intrastromal arcuate incisions (energy 1.8 µJ, spot line separation 2 × 2 µm) were performed in cadaver eyes. Optical coherence tomography was performed immediately after surgery and the corneas were fixed for light scanning and transmission electron microscopy. RESULTS: The rabbit model showed anterior stromal inflammation with epithelial hyperplasia in penetrating blade and laser penetrating wounds. The laser intrastromal and penetrating incisions showed localized constriction of the stromal layers of the cornea near the wound. In cadaver eyes, penetrating wound morphology was similar between blade and laser whereas intrastromal wounds did not affect the cornea above or below incisions. CONCLUSION: Penetrating femtosecond laser arcuate incisions have more predictable and controlled outcomes shown by less post-operative scarring than incisions performed with a diamond blade. Intrastromal incisions do not affect uncut corneal layers as demonstrated by histopathology. The femtosecond laser has significant advantages in its ability to make intrastromal incisions which are not achievable by traditional freehand or mechanical diamond blades.

Impaired working memory capacity is not caused by failures of selective attention in schizophrenia.

The cognitive impairments associated with schizophrenia have long been known to involve deficits in working memory (WM) capacity. To date, however, the causes of WM capacity deficits remain unknown. The present study examined selective attention impairments as a putative contributor to observed capacity deficits in this population. To test this hypothesis, we used an experimental paradigm that assesses the role of selective attention in WM encoding and has been shown to involve the prefrontal cortex and the basal ganglia. In experiment 1, participants were required to remember the locations of 3 or 5 target items (red circles). In another condition, 3-target items were accompanied by 2 distractor items (yellow circles), which participants were instructed to ignore. People with schizophrenia (PSZ) exhibited significant impairment in memory for the locations of target items, consistent with reduced WM capacity, but PSZ and healthy control subjects did not differ in their ability to filter the distractors. This pattern was replicated in experiment 2 for distractors that were more salient. Taken together, these results demonstrate that reduced WM capacity in PSZ is not attributable to a failure of filtering irrelevant distractors.

Comparison of wavefront aberrations in rabbit and human eyes.

BACKGROUND: The rabbit is one of the most common animal models used for preclinical safety evaluation of new cataract surgery and laser vision-correction technologies in ophthalmic research; however, the distributions of wavefront aberrations in rabbit eyes are unknown. The purpose of this study was to investigate the similarities and differences of wavefront aberrations between rabbit and human eyes. METHODS: Monochromatic wavefront aberrations of left and right eyes of 12 rabbits and 12 human subjects with normal vision were measured by a commercial aberrometer (WaveScan Wavefront System, Abbott Medical Optics Inc, California, USA). Comparison of wavefront aberrations in rabbit and human eyes is based on a 6.0 mm pupil. RESULTS: The rabbit eyes have an average spherical refraction of 1.51 ± 0.83 D and a cylindrical refraction of -1.03 ± 0.63 D. The average spherical refractive error of the human eyes used in this study was -2.03 ± 2.59 D with a cylindrical refraction of -1.27 ± 1.01 D. The average wavefront error root-mean-square (RMS) from higher-order aberrations is 0.34 µm in rabbits (6.0 mm pupil), which is higher compared to the wavefront error RMS value of human eyes (0.26 µm). The largest higher-order aberration in rabbit eyes is vertical coma (Z7, 0.19 ± 0.16 µm), whereas the largest higher-order aberration in human eyes is spherical aberration (Z12, 0.07 ± 0.13 µm). Wavefront error RMS, vertical coma and some higher-order aberrations are significantly correlated between the right and left rabbit eye. CONCLUSION: Compared to wavefront aberrations in the human eye measured in this study, the rabbit eye has less refractive error but larger higher-order aberrations both in wavefront error RMS and some higher-order aberration terms. Similar to human eyes, wavefront error and some higher-order aberrations are significantly correlated between the right and left rabbit eye.

Interview: Interview with Brad Gray for Personalized Medicine.

On 29 June 2010 Brad Gray became the President and Chief Executive Officer of the privately held life sciences company NanoString Technologies, WA, USA. Previously the Vice President of Product and Business Development at Genzyme Genetics, the diagnostic services division of Genzyme Corporation, Brad was in charge of developing molecular diagnostics and partnering activities. In December 2010, NanoString announced its securing of an exclusive worldwide license to develop in vitro diagnostic and research products for breast cancer intrinsic subtyping with the PAM50 gene signature. Brad Gray received a BA in Economics and Management from Oxford University, where he studied as a British Marshall Scholar, and an SB in Chemical Engineering from the Massachusetts Institute of Technology. Brad was also a management consultant in the healthcare practice of McKinsey & Company.